US4476306A - Method of preparing 2,4-dihydroxypyrimidine - Google Patents

Method of preparing 2,4-dihydroxypyrimidine Download PDF

Info

Publication number
US4476306A
US4476306A US06/401,294 US40129482A US4476306A US 4476306 A US4476306 A US 4476306A US 40129482 A US40129482 A US 40129482A US 4476306 A US4476306 A US 4476306A
Authority
US
United States
Prior art keywords
acid
hydroxypyrimidine
uracil
carboxymethylthio
alkali salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
US06/401,294
Other languages
English (en)
Inventor
Hermann Peeters
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dynamit Nobel AG
Original Assignee
Dynamit Nobel AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dynamit Nobel AG filed Critical Dynamit Nobel AG
Assigned to DYNAMIT NOBEL AG; 521 TROISDOF BEZ. KOELN WEST GERMANY A CORP. reassignment DYNAMIT NOBEL AG; 521 TROISDOF BEZ. KOELN WEST GERMANY A CORP. ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: PEETERS, HERMANN
Application granted granted Critical
Publication of US4476306A publication Critical patent/US4476306A/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/56—One oxygen atom and one sulfur atom

Definitions

  • This invention relates to the preparation of 2,4-dihydroxypyrimidine, also known as "uracil”.
  • the process involves the preparation of uracil from alkali formyl acetic esters in a four-step synthesis, without isolation of intermediate products, in accordance with the following scheme: ##STR1##
  • Uracil is a product that is widely used as an industrial chemical, in biochemistry, and in agricultural chemistry (Ind. Chem. Prod. Res. Dev., Vol. 17 No. 4 (1978)).
  • 2-Carboxymethylthio-4-hydroxy-pyrimidine is a chemical intermediate that can be transformed to uracil or can serve as a starting product for a variety of pharmaceutically active pyrimidine derivatives.
  • Uracil can be made by a variety of methods. Low yields of about 55% are obtained by the reaction of malic acid with urea in the presence of 115% of oleum (J. Amer. Chem. Soc. 48 (1926) 2379). Large amounts of dilute sulfuric acid are produced and this is undesirable.
  • 2-Carboxymethylthio-4-hydroxypyrimidine can be obtained in a 70% yield by the reaction of 2-mercapto-4-hydroxypyrimidine in aqueous alkaline medium with chloroacetic acid, followed by acidification (C. A. 52 (1958) 18702 h).
  • alkali formyl acetic acid alkyl ester is reacted first to the alkali salt of 4-mercapto-4-hydroxypyrimidine, for example in accordance with U.S. Pat. No. 3,718,649, and the latter is further reacted directly with chloroacetic acid.
  • an alkali formyl acetic acid alkyl ester in solid form or dissolved in polar solvents containing water, can be proportioned into an aqueous solution of alkali hydroxide and thiourea, preferably in water, at temperatures from about 10° to 25° C., and brought to reaction in the temperature range from 20° to 180° C. in approximately 1 to 2 hours.
  • the amount of alkali hydroxide should be from 1 to 8 mol, preferably 2 to 5 mol, per mol of thiourea.
  • the concentration of the reaction solution as regards thiourea should amount to from 0.2 to 6 mol/l, preferably 0.5 to 4 mol/l.
  • the molar ratio of thiourea to alkali formyl acetic ester should be approximately 1:1.
  • Me can be an alkali metal, very preferably sodium or, less preferably, potassium, and alkyl can be a preferably saturated alkyl moiety of 1 to 8 carbon atoms, very preferably methyl or ethyl.
  • the reaction product is the alkali salt of 4-hydroxy-2-mercaptopyrimidine, which is easily soluble in water.
  • This product is directly reacted with chloroacetic acid with cooling, at about 20° to 30° C., as described above. Further addition of alkali or water is unnecessary.
  • the molar ratio of chloroacetic acid to the thiourea put in should be from 2:1 to 0.5 to 1, advantageously 1.5:1 to 0.75:1, or from 3 moles to 1 mole, preferably 1.5 moles to 1 mole, per mole of 4-hydroxy-2-mercaptopyrimidine alkali salt.
  • 2-Carboxymethylthio-4-hydroxypyrimidine forms as salt, from the solution of which the free compound is precipitated by acidification with mineral acids such as sulfuric acid or hydrochloric acid or with chloroacetic acid, and adjustment to a pH of 7 or less, in some cases less than pH 3.
  • Uracil is obtained by adjusting the solution of the alkali salt of 2-carboxymethylthio-4-hydroxypyrimidine with acids, especially mineral acid such as sulfuric acid or hydrochloric acid, or with chloroacetic acid, to a pH of 7 or less, preferably of less than 3, and then heating at 50° to 200° C., advantageously at 100° C. From 1 to 30 equivalents, and very preferably 1 to 10 equivalents, of acid are used.
  • acids especially mineral acid such as sulfuric acid or hydrochloric acid, or with chloroacetic acid
  • the reaction time amounts to from 1 to no more than 5 hours.
  • the uracil is produced in the form of a product insoluble in water, which is filtered out, washed with water and dried.
  • the mercaptoacetic acid that is formed can be obtained by extraction of the mother liquor.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US06/401,294 1981-07-23 1982-07-23 Method of preparing 2,4-dihydroxypyrimidine Expired - Fee Related US4476306A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19813130455 DE3130455A1 (de) 1981-07-23 1981-07-23 Verfahren zur herstellung von 2,4-dihydroxypyrimidin (uracil)
DE3130455 1981-07-23

Publications (1)

Publication Number Publication Date
US4476306A true US4476306A (en) 1984-10-09

Family

ID=6138323

Family Applications (1)

Application Number Title Priority Date Filing Date
US06/401,294 Expired - Fee Related US4476306A (en) 1981-07-23 1982-07-23 Method of preparing 2,4-dihydroxypyrimidine

Country Status (5)

Country Link
US (1) US4476306A (ja)
EP (1) EP0071018B1 (ja)
JP (1) JPS5824570A (ja)
AT (1) ATE17348T1 (ja)
DE (2) DE3130455A1 (ja)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4558126A (en) * 1983-11-24 1985-12-10 Dynamit Nobel Ag Method of preparing uracil
CN112979560A (zh) * 2021-03-12 2021-06-18 爱斯特（成都）生物制药股份有限公司 一种制备高收率、高纯度的尿嘧啶的方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2417318A (en) * 1945-07-09 1947-03-11 American Cyanamid Co Method of producing 4-hydroxy pyrimidines
US3718649A (en) * 1970-10-05 1973-02-27 Polaroid Corp Process for thiouracil production

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2417318A (en) * 1945-07-09 1947-03-11 American Cyanamid Co Method of producing 4-hydroxy pyrimidines
US3718649A (en) * 1970-10-05 1973-02-27 Polaroid Corp Process for thiouracil production

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4558126A (en) * 1983-11-24 1985-12-10 Dynamit Nobel Ag Method of preparing uracil
CN112979560A (zh) * 2021-03-12 2021-06-18 爱斯特（成都）生物制药股份有限公司 一种制备高收率、高纯度的尿嘧啶的方法

Also Published As

Publication number Publication date
EP0071018B1 (de) 1986-01-08
DE3268384D1 (en) 1986-02-20
ATE17348T1 (de) 1986-01-15
DE3130455A1 (de) 1983-02-10
EP0071018A1 (de) 1983-02-09
JPS5824570A (ja) 1983-02-14

Similar Documents

Publication Publication Date Title
US4977264A (en) Process for the production of 4,5-dichloro-6-ethylpyrimidine
US4670191A (en) Process for the preparation of N-phosphonomethylglycine
JP2975455B2 (ja) アラントインの製造方法
US4476306A (en) Method of preparing 2,4-dihydroxypyrimidine
HU200446B (en) Process for production of 1-alkyl-5-nitro-imidasoles
US4558126A (en) Method of preparing uracil
US4275216A (en) Process for preparing 4(5)-hydroxymethyl 5(4)-lower alkyl imidazoles
US2766255A (en) alpha-methyltryptophane and salts thereof
US4841092A (en) Preparation of tris(2-cyanoethyl)amine
US4521616A (en) Method for the preparation of fluoroanthranilic acids
KR920002127B1 (ko) 6-아미노-1,2-디히드로-1-히드록시-2-이미노-4-피페리디노피리미딘의 제조방법
CZ266192A3 (en) Process for preparing 2-(methylthio)-disodium barbiturate
KR890002253B1 (ko) 티아졸 화합물의 제조방법
JPH0573738B2 (ja)
US2861996A (en) Process of preparing serines
RU1824401C (ru) Способ получени 5-метил-2-тиоурацила
JP2708617B2 (ja) ４，４―ジアルキル置換チアゾリジンチオンの製造方法
US2362070A (en) Preparation of isocytosine
US4550193A (en) Process for the preparation of 2,3-dimercaptosuccinic acid and its lower alkyl esters
CA1042915A (en) 2-iminomethyl-3',4',5'-trimethoxycinnamic acids and esters thereof, and their production
US4267333A (en) Preparation of 2-trifluoromethyl cinchoninic acids
KR0157368B1 (ko) 4-메틸-7-히드록시쿠마린의 상업적 제조방법
KR800000746B1 (ko) 5-설파모일-안트라닐산의 제조방법
US4401814A (en) Adenine preparation
CA1066291A (en) 3-formyl-4-methyl-2,6-dihydroxypyridine and a process for its preparation

Legal Events

Date Code Title Description
AS Assignment

Owner name: DYNAMIT NOBEL AG; 521 TROISDOF BEZ. KOELN WEST GER

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:PEETERS, HERMANN;REEL/FRAME:004025/0056

Effective date: 19820607

REMI Maintenance fee reminder mailed
LAPS Lapse for failure to pay maintenance fees
STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362

FP Lapsed due to failure to pay maintenance fee

Effective date: 19881009